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Cited by 14Liver Disease Diagnosis and TreatmentSphingolipid Metabolism and SignalingLipid metabolism and biosynthesis

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Effect of FTY720P on lipid accumulation in HEPG2 cells

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Rida, Reem, Kreydiyyeh, Sawsan·2023·Scientific Reports
DOI 10.1038/s41598-023-46011-4PMC PMC10641067
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Abstract

Nonalcoholic fatty liver disease (NAFLD) is characterized by an increase in hepatic lipid accumulation due to impaired lipid metabolism. Although a correlation was found between NAFLD and sphingosine-1-phosphate (S1P), the role of the sphingolipid remains controversial. The aim of this study was to investigate any involvement of S1P in steatosis using its analog FTY720P and HepG2 cells. Lipid accumulation was induced by incubating the cells in a mixture of oleic and palmitic acid, and was quantified using Oil Red O. The involvement of signaling mediators was studied using pharmacological inhibitors and western blot analysis. FTY720P increased lipid accumulation, but this increase wasn't maintained in the presence of inhibitors of S1PR3, Gq, SREBP, mTOR, PI3K, and PPARγ indicating their involvement in the process. The results revealed that FTY720P binds to S1PR3 which activates sequentially Gq, PI3K, and mTOR leading to an increase in SREBP expression and PPARγ activation. It was concluded that in presence of a high level of fatty acids, lipid accumulation is increased in hepatocytes by the exogenously added FTY720P.

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Figure 1 Fatty acids induce lipid accumulation in HepG2 cells. (a) The presence of FAs in the incubation medium increased lipid accumulation and (b) lipid droplets appeared stained red with Oil Red O as seen under the microscope (40x). Values are means ± SEM; N = 3. *Significantly different from the control at P < 0.05.
Figure 1 Fatty acids induce lipid accumulation in HepG2 cells. (a) The presence of FAs in the incubation medium increased lipid accumulation and (b) lipid droplets appeared stained red with Oil Red O as seen under the microscope (40x). Values are means ± SEM; N = 3. *Significantly different from the control at P < 0.05.CC BY · PubMed Central
Figure 2 S1P and FTY720P induce lipid accumulation in HepG2 cells. Lipid accumulation in the presence of (a) Sphk1 inhibitor PF543; (b) blockers of all S1PRs. Values are means ± SEM. N = 4. Bars not sharing a common letter are considered significantly different from each other at P < 0.05; c) various concentrations of the S1P analog FTY720P. Values are means ± SEM; N = 3. *Significantly different from the control at P < 0.05.
Figure 2 S1P and FTY720P induce lipid accumulation in HepG2 cells. Lipid accumulation in the presence of (a) Sphk1 inhibitor PF543; (b) blockers of all S1PRs. Values are means ± SEM. N = 4. Bars not sharing a common letter are considered significantly different from each other at P < 0.05; c) various concentrations of the S1P analog FTY720P. Values are means ± SEM; N = 3. *Significantly different from the control at P < 0.05.CC BY · PubMed Central
Figure 3 Effect of FTY720P on lipid accumulation in the presence of (a) S1PR1 blocker W146. (b) S1PR2 blocker JTE 013. (c) S1PR4 blocker CYM50358. Values are means ± SEM; N = 5. Bars not sharing a common letter are considered significantly different from each other at P < 0.05.
Figure 3 Effect of FTY720P on lipid accumulation in the presence of (a) S1PR1 blocker W146. (b) S1PR2 blocker JTE 013. (c) S1PR4 blocker CYM50358. Values are means ± SEM; N = 5. Bars not sharing a common letter are considered significantly different from each other at P < 0.05.CC BY · PubMed Central
Figure 4 S1PR3 and Gq mediate the FTY720P effect on lipid accumulation. (a) Effect of FTY720P on lipid accumulation in the presence of S1PR3 blocker CAY10444. (b) Effect of FTY720P on lipid accumulation in the presence of the Gq inhibitor YM254890. (c) Protein expression of S1PR3. The blot is representative of an experiment repeated 3 times. Values were normalized to GAPDH and reported as arbitrary densitometry units. All values are means ± SEM; N = 3. Bars not sharing a common letter are considered significantly different from each other at P < 0.05.
Figure 4 S1PR3 and Gq mediate the FTY720P effect on lipid accumulation. (a) Effect of FTY720P on lipid accumulation in the presence of S1PR3 blocker CAY10444. (b) Effect of FTY720P on lipid accumulation in the presence of the Gq inhibitor YM254890. (c) Protein expression of S1PR3. The blot is representative of an experiment repeated 3 times. Values were normalized to GAPDH and reported as arbitrary densitometry units. All values are means ± SEM; N = 3. Bars not sharing a common letter are considered significantly different from each other at P < 0.05.CC BY · PubMed Central
Figure 5 Effect of FTY720P on lipid accumulation in the presence of (a) the PI3K inhibitor wortmannin. (b) the mTOR inhibitor rapamycin. All values are means ± SEM; N = 4. Bars not sharing a common letter are considered significantly different from each other at P < 0.05.
Figure 5 Effect of FTY720P on lipid accumulation in the presence of (a) the PI3K inhibitor wortmannin. (b) the mTOR inhibitor rapamycin. All values are means ± SEM; N = 4. Bars not sharing a common letter are considered significantly different from each other at P < 0.05.CC BY · PubMed Central
Figure 6 Effect of FTY720P on lipid accumulation in the presence of (a) the SREBP inhibitor fatostatin. (b) The PPARγ inhibitor GW9662. Values are means ± SEM; N = 5. Bars not sharing a common letter are considered significantly different from each other at P < 0.05.
Figure 6 Effect of FTY720P on lipid accumulation in the presence of (a) the SREBP inhibitor fatostatin. (b) The PPARγ inhibitor GW9662. Values are means ± SEM; N = 5. Bars not sharing a common letter are considered significantly different from each other at P < 0.05.CC BY · PubMed Central
Figure 7 (a) Effect of the SREBP inhibitor fatostatin on lipid accumulation in the presence of the PPARγ agonist rosiglitazone. Values are means ± SEM; N = 5. (b) Effect of PPARγ inhibition on the protein expression of SREBP. (c) Effect of SREBP inhibition on the protein expression of p-PPARγ. The blot is representative of an experiment repeated 3 times. Values were normalized to GAPDH and reported as arbitrary densitometry units. Values are means ± SEM; N = 3. Bars not sharing a common letter are considered significantly different from each other at P < 0.05.
Figure 7 (a) Effect of the SREBP inhibitor fatostatin on lipid accumulation in the presence of the PPARγ agonist rosiglitazone. Values are means ± SEM; N = 5. (b) Effect of PPARγ inhibition on the protein expression of SREBP. (c) Effect of SREBP inhibition on the protein expression of p-PPARγ. The blot is representative of an experiment repeated 3 times. Values were normalized to GAPDH and reported as arbitrary densitometry units. Values are means ± SEM; N = 3. Bars not sharing a common letter are considered significantly different from each other at P < 0.05.CC BY · PubMed Central
Figure 8 (a) Lipid accumulation in the simultaneous presence of fatostatin and the mTOR agonist MHY1485. Values are means ± SEM. N = 5. (b) Effect of inhibitors of mTOR, PI3K, and Gq on the protein expression of SREBP. Values were normalized to GAPDH and reported as arbitrary densitometry units. Values are means ± SEM. N = 3. Bars not sharing a common letter are considered significantly different from each other at P < 0.05.
Figure 8 (a) Lipid accumulation in the simultaneous presence of fatostatin and the mTOR agonist MHY1485. Values are means ± SEM. N = 5. (b) Effect of inhibitors of mTOR, PI3K, and Gq on the protein expression of SREBP. Values were normalized to GAPDH and reported as arbitrary densitometry units. Values are means ± SEM. N = 3. Bars not sharing a common letter are considered significantly different from each other at P < 0.05.CC BY · PubMed Central
Figure 9 (a) Effect of mTOR inhibition with rapamycin on lipid accumulation in the presence of the PPARγ agonist rosiglitazone. (b) Effect of the mTOR agonist MHY 1485 on lipid accumulation in the presence of the PPARγ inhibitor GW9662. Values are means ± SEM. N = 5. c) Protein expression of p-PPARγ in the presence of inhibitors of mTOR, PI3K, and Gq. Values were normalized to GAPDH and reported as arbitrary densitometry units. Values are means ± SEM. N = 3. Bars not sharing a common letter are considered significantly different from each other at P < 0.05.
Figure 9 (a) Effect of mTOR inhibition with rapamycin on lipid accumulation in the presence of the PPARγ agonist rosiglitazone. (b) Effect of the mTOR agonist MHY 1485 on lipid accumulation in the presence of the PPARγ inhibitor GW9662. Values are means ± SEM. N = 5. c) Protein expression of p-PPARγ in the presence of inhibitors of mTOR, PI3K, and Gq. Values were normalized to GAPDH and reported as arbitrary densitometry units. Values are means ± SEM. N = 3. Bars not sharing a common letter are considered significantly different from each other at P < 0.05.CC BY · PubMed Central
Figure 10 (a) Effect of the mTOR agonist MHY 1485 on lipid accumulation in presence of the PI3K inhibitor wortmannin. Values are means ± SEM; N = 3. (b) Protein expression of p-mTOR in presence of inhibitors of PI3K and Gq. Values were normalized to GAPDH and reported as arbitrary densitometry units. Values are means ± SEM; N = 3. Bars not sharing a common letter are considered significantly different from each other at P < 0.05.
Figure 10 (a) Effect of the mTOR agonist MHY 1485 on lipid accumulation in presence of the PI3K inhibitor wortmannin. Values are means ± SEM; N = 3. (b) Protein expression of p-mTOR in presence of inhibitors of PI3K and Gq. Values were normalized to GAPDH and reported as arbitrary densitometry units. Values are means ± SEM; N = 3. Bars not sharing a common letter are considered significantly different from each other at P < 0.05.CC BY · PubMed Central
Figure 11 (a) Effect of the PI3K inhibitor wortmannin on lipid accumulation in the presence of the PPARγ agonist rosiglitazone. Values are means ± SEM; N = 3. (b) Protein expression of p-Akt in presence of an inhibitor of SREBP or PPARγ. The blots are representative of an experiment repeated 3 times. Values were normalized to GAPDH and reported as arbitrary densitometry units. Values are means ± SEM; N = 3. Bars not sharing a common letter are considered significantly different from each other at P < 0.05.
Figure 11 (a) Effect of the PI3K inhibitor wortmannin on lipid accumulation in the presence of the PPARγ agonist rosiglitazone. Values are means ± SEM; N = 3. (b) Protein expression of p-Akt in presence of an inhibitor of SREBP or PPARγ. The blots are representative of an experiment repeated 3 times. Values were normalized to GAPDH and reported as arbitrary densitometry units. Values are means ± SEM; N = 3. Bars not sharing a common letter are considered significantly different from each other at P < 0.05.CC BY · PubMed Central
Figure 12 Protein expression of p-Akt in presence of an inhibitor of Gq. The blots are representative of an experiment repeated 3 times. Values were normalized to GAPDH and reported as arbitrary densitometry units. Values are means ± SEM; N = 3. Bars not sharing a common letter are considered significantly different from each other at P < 0.05.
Figure 12 Protein expression of p-Akt in presence of an inhibitor of Gq. The blots are representative of an experiment repeated 3 times. Values were normalized to GAPDH and reported as arbitrary densitometry units. Values are means ± SEM; N = 3. Bars not sharing a common letter are considered significantly different from each other at P < 0.05.CC BY · PubMed Central
Figure 13 The signaling pathway activated by FTY720P.
Figure 13 The signaling pathway activated by FTY720P.CC BY · PubMed Central

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Metadata

Authors
Rida, R., & Kreydiyyeh, S.
Affiliations
American University of Beirut (LB)
Corresponding author
Kreydiyyeh, Sawsan
ORCID
Kreydiyyeh, Sawsan
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2023-11-12
Volume
13
Issue
1
Pages
19716-19716
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/s41598-023-46011-4
PMC
PMC10641067
OpenAlex
W4388609714
Cited by
14
References
56
Citations by year
2026: 9 · 2025: 4 · 2024: 1
FWCI
2.80
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
University Research Board, American University of Beirut
Topics
  • Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords
sphingosine-1-phosphate, non-alcoholic fatty liver disease, hepatic steatosis, lipid accumulation, S1PR3, Gq signaling, phosphatidylinositol 3-kinase, mTOR, SREBP, PPARγ, hepatocytes, oleic acid, palmitic acid
MeSH terms
Humans, Liver, Lysophospholipids, Organophosphates, Sphingosine, Phosphatidylinositol 3-Kinases, PPAR gamma, Lipid Metabolism, Sterol Regulatory Element Binding Protein 1, Hep G2 Cells, TOR Serine-Threonine Kinases, Non-alcoholic Fatty Liver Disease

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Rida, R., & Kreydiyyeh, S. (2023). Effect of FTY720P on lipid accumulation in HEPG2 cells. Scientific Reports. https://doi.org/10.1038/s41598-023-46011-4